Recent Developments in the Role of Histone Acetylation in Asthma.

BACKGROUND: Epigenetic modifications are known to mediate both beneficial and unfavorable effects of environmental exposures on the development and clinical course of asthma. On the molecular level, epigenetic mechanisms participate in multiple aspects of the emerging and ongoing asthma pathology. SUMMARY: Studies performed in the last several years expand our knowledge on the role of histone acetylation, a classical epigenetic mark, in the regulation of (patho)physiological processes of diverse cells playing a central role in asthma, including those belonging to the immune system (e.g., CD4+ T cells, macrophages) and lung structure (e.g., airway epithelial cells, pulmonary fibroblasts). Those studies demonstrate a number of specific histone acetylation-associated mechanisms and pathways underlying pathological processes characteristic for asthma, as well as report their modification modalities. KEY MESSAGES: Dietary modulation of histone acetylation levels in the immune system might protect against the development of asthma and other allergies. Interfering with the enzymes controlling the histone acetylation status of structural lung and (local) immune cells might provide future therapeutic options for asthmatics. Despite some methodological obstacles, analysis of the histone acetylation levels might improve asthma diagnostics.

Fibrin clot properties and fibrinolysis in patients with endocrine hypertension due to aldosterone or catecholamines excess.

OBJECTIVE: The aim of the study was to investigate a new possible background of increased risk of cardiovascular events in two forms of endocrine hypertension: in primary aldosteronism (PA) and pheochromocytoma/paraganglioma (PPGL) in comparison to essential hypertension (EHT). CONTEXT: Prothrombotic properties of the fibrin clot structure, impaired fibrinolysis and enhanced thrombin generation have been reported to be associated with increased cardiovascular risk. DESIGN: Patients with PA and PPGL were evaluated at baseline and re-evaluated 3 months after causative treatment. At baseline PA and PPGL patients were compared to matched EHT patients and to healthy controls. PATIENTS: The study included 35 patients with PA, 16 patients with PPGL and two reference groups of patients with EHT (32 and 22 patients) and healthy controls (35 and 23 subjects). MEASUREMENTS: All subjects underwent evaluation according to the study protocol that included plasma fibrin clot permeability (Ks), clot lysis time, endogenous thrombin potential. RESULTS: There were no differences in clot structure and fibrinolytic activity in PA and PPGL patients as compared to matched patients with EHT, whereas all hypertensive groups were characterized by more compact fibrin clot structure, faster clot formation and enhanced thrombin generation in comparison to healthy controls. Both in PA and PPGL patients, fibrin clot properties and fibrinolytic parameters remained stable after the causative treatment. CONCLUSIONS: Patients with PA and PPGL are at a prothrombic state comparable to patients with EHT. The results suggest the higher risk of cardiovascular events observed in hypertensive PA and PPGL as compared to EHT is not mediated through investigated prothrombic mechanisms.

Fibrinogen ß chain and FXIII polymorphisms affect fibrin clot properties in acute pulmonary embolism.

BACKGROUND: Prothrombotic fibrin clot properties, including increased clot density, are in part genetically determined. We investigated whether fibrinogen alpha-chain gene (FGA) c.991A>G (rs6050), fibrinogen beta chain gene (FGB) -455G>A (rs1800790) and factor XIII gene (F13) c.103G>T (rs5985) polymorphisms affect plasma fibrin clot properties in patients with acute pulmonary embolism (PE). METHODS: As many as 126 normotensive patients with PE, free of cancer, were genotyped by TaqMan assay. Fibrin clot permeability (Ks ), clot lysis time (CLT) and endogenous thrombin potential (ETP) were assessed on admission. RESULTS: The minor allele frequencies were as follows: FGA rs6050 (n = 62, 0.31), FGB rs1800790 (n = 40, 0.17) and F13 rs5985 (n = 49, 0.23). There were no differences related to any of the polymorphisms with regard to demographic, clinical and laboratory data, except for fibrinogen concentration, which was higher in carriers of F13 rs5985 polymorphism (p = .024), and PE combined with deep-vein thrombosis, which was less prevalent in FGB rs1800790 polymorphism carriers (p = .004). Carriers of FGB rs1800790 A allele and F13 rs5985 T allele had lower Ks , prolonged CLT and higher ETP compared with major homozygotes (all p < .05). After adjustment for fibrinogen, all differences remained significant (all p < .01). There were no associations between the FGA rs6050 polymorphism and Ks , CLT or ETP. CONCLUSION: Our study showed that FGB rs1800790 and F13 rs5985 polymorphisms contribute to the prothrombotic fibrin clot phenotype and these effects are strong enough to be observed in the acute phase of PE.

Impaired fibrin clot lysis is associated with increased mortality in patients after coronary artery bypass grafting: A long-term follow-up study.

BACKGROUND: Mortality after coronary artery bypass grafting (CABG) is primarily thromboembolic by nature. We investigated whether impaired fibrinolysis observed in cardiovascular diseases is associated with long-term mortality following CABG. METHODS: The study population comprised 292 consecutive patients (aged 64.6 ± 8.1 years) who underwent scheduled CABG. We measured plasma clot lysis time (CLT) preoperatively as a measure of fibrinolysis capacity. Cardiovascular and all-cause deaths were recorded during a median follow-up of 13.8 years. RESULT: CLT positively correlated with age (r = .56, p < .001), fibrinogen (r = .25, p = .002) and EuroSCORE I (r = .32, p < .001). The cardiovascular and overall mortality rates were 3.0 and 4.9 per 100 patient-years (32.4% vs 52.8%) respectively. In patients who died from cardiovascular and all causes, CLT was prolonged compared with survivors (both p < .050). Multivariable Cox regression analysis adjusted for potential confounders showed that long-term cardiovascular and all-cause deaths were associated with CLT (HR per 10 min 1.206; 95% CI 1.037-1.402, p = .015 and HR 1.164; 96% CI 1.032-1.309, p = .012), low-density lipoprotein cholesterol (HR per 1 mmol/L 1.556; 95% CI 1.205-2.010, p < .001 and HR 1.388; 96% CI 1.125-1.703, p = .002), C-reactive protein (HR per 10 mg/L 1.171; 95% CI 1.046-1.312, p = .006 and HR 1.127; 95% CI 1.005-1.237, p = .022) and EuroSCORE I (HR 1.173; 95% CI 1.016-1.355, p = .030 and HR 1.183; 95% CI 1.059-1.317, p = .003 respectively). Type 2 diabetes was solely associated with overall mortality (HR 1.594; 96% CI 1.088-2.334, p = .017). CONCLUSIONS: In this study, we showed that reduced fibrin clot susceptibility to fibrinolysis is weekly associated with long-term mortality in advanced CAD.

Afibrinogenemia caused by a novel homozygous missense mutation, FGB p.Cys241Tyr, in a male patient with recurrent intracranial bleeding: case report and review of literature.

INTRODUCTION: Congenital afibrinogenemia is a severe bleeding disorder, sometimes manifesting as thrombosis and/or pregnancy complications. Intracranial haemorrhage (ICH) constitutes the major cause of death in this disease. METHODS: We present the case of a male patient with congenital afibrinogenemia, who presented with recurrent intracranial hemorrhages, despite prophylactic fibrinogen substitution. We also review the literature for the risk of intracranial hemorrhages in afibrinogenemia. RESULT: Molecular analysis revealed a novel homozygous missense mutation in FGB exon 5, p.Cys241 Tyr, that was named "Fibrinogen Krakow V". DISCUSSION AND CONCLUSION: Intracranial hemorrhage is a severe manifestation of afibrinogenemia, also in children. The clinical presentation of afibrinogenemia is variable. Fibrinogen substitution carries a risk of thrombotic complications.

Novel Splice Site Mutation in the PROS1 Gene in a Polish Patient with Venous Thromboembolism: c.602-2delA, Splice Acceptor Site of Exon 7.

We identified a novel splice site mutation of the PROS1 gene in a Polish family with protein S (PS) deficiency and explored the molecular pathogenesis of this previously undescribed variant. A novel mutation was detected in a 26-year-old woman with a history of venous thromboembolism (VTE) provoked by oral contraceptives. Her family history of VTE was positive. The sequence analysis of the PROS1 gene was performed in the proband and the proband's family. The proband and their asymptomatic father had lower free PS levels (45% and 50%, respectively) and PS activity (48% and 44%, respectively). Total PS levels were normal (65.6% and 62.4%, respectively). The sequence analysis of the PROS1 gene revealed the presence of heterozygous deletion at the nucleotide position c.602-2 in intron 6, just upstream of exon 7, detected in the proband and her father. This variant alters the splice acceptor site of exon 7, and, according to the in silico prediction, it is highly likely to cause in-frame exon 7 skipping. We also presented follow-up data of two other Polish patients with PS deficiency associated with splice site mutations in PROS1 gene.

Direct oral anticoagulants in the treatment of cerebral venous sinus thrombosis: a single institution's experience.

AIM OF THE STUDY: Oral anticoagulants, preferentially vitamin K antagonists (VKA), are recommended for 3-12 months in patients with cerebral venous sinus thrombosis (CVST). We present a series of patients with CVST treated with direct oral anticoagulants (DOAC). MATERIALS AND METHODS: We prospectively recruited 36 patients with CVST (aged 40.3 ± 9.2 years, 58.3% female) treated with DOAC based on the physician's or patient's preferences. Functional outcome was assessed with modified Rankin Scale. Recanalisation was assessed on imaging at 3-6 months post the event. Patients were followed for a median of 30 [interquartile range (IQR) 25-37] months. RESULTS: After use of heparin (median: 6 days; IQR 5-8.75), patients received dabigatran (150 mg bid, n = 16 or 110 mg bid, n = 2), rivaroxaban (20 mg qd, n = 10) or apixaban (5 mg bid, n = 8) for a median of 8.5 months (IQR 6.25-12). Complete or partial recanalisation was observed in 34 cases (94.4%). Three patients (8.3%) experienced major bleeding: menorrhagia on rivaroxaban (n = 2) and gastrointestinal bleeding on dabigatran (n = 1). A favourable functional outcome was observed in 24 (66.7%) patients, without any fatality. CSVT recurred in two patients (5.6%) and two venous thromboses developed in two other patients with inherited thrombophilia after anticoagulation withdrawal. CONCLUSIONS AND CLINICAL IMPLICATIONS: DOACs could be an alternative to VKA in CVST patients.

Alpha-2-antiplasmin Arg407Lys polymorphism and cryptogenic ischemic cerebrovascular events: Association with neurological deficit.

OBJECTIVE: Genetic background of cryptogenic ischemic stroke (IS) and transient ischemic attack (TIA) remains uncertain. Alpha-2-antiplasmin (α2AP) Arg407Lys polymorphism has been shown to be less common in patients with abdominal aortic aneurysm (AAA) compared with healthy controls. We investigated associations of α2AP Arg407Lys polymorphism with cryptogenic IS and TIA. METHODS: We studied 165 consecutive Caucasian patients who experienced cryptogenic IS (n=123) or TIA (n=42). Neurological outcomes were assessed using the modified Rankin Scale (mRS) in the acute phase of cerebral ischemia and 8 (6-12) months after the index episode. Patients were genotyped for α2AP Arg407Lys polymorphism (rs1057335) using real time PCR technique. RESULTS: The allele frequency of Arg407Lys polymorphism was: 0.82/0.18. The 407Lys allele was more frequent in TIA patients compared to the IS group (0.29 vs. 0.14, p=0.003). In the whole group, as well as in IS and TIA patients analyzed separately, possession of the 407Lys allele was associated with excellent outcome (mRS 0-1) during follow-up (p<0.05) but not in the acute phase of ischemic events both in thrombolyzed and nonthrombolyzed IS patients. The multivariate logistic regression model showed that the excellent outcome (mRS 0-1) assessed after 8 (6-12) months since the index cerebral ischemia was predicted by the occurrence of Lys407 allele (OR 6.18, 95% CI, 2.01-18.98, p=0.001). CONCLUSION: The presence of 407Lys allele is associated with better prognosis in cryptogenic cerebrovascular events. Our findings suggest that the α2AP Arg407Lys polymorphism could be involved in the pathogenesis of cerebral ischemia and its outcomes.

12-month patterns of serum markers of collagen synthesis, transforming growth factor and connective tissue growth factor are similar in new-onset and chronic dilated cardiomyopathy in patients both with and without cardiac fibrosis.

BACKGROUND: The dynamics of the extracellular matrix (ECM) fibrosis process in dilated cardiomyopathy (DCM) may be assessed non-invasively by means of serum markers of fibrosis. AIM: To explore the kinetics of serum markers of fibrosis during a 12-month follow-up in DCM. METHODS: We included 70 consecutive DCM patients (pts) (48±12.1years, EF 24.4±7.4%) with new-onset (n=35, duration <6months) and chronic DCM (n=35, >6months). Markers of collagen type I and III synthesis - procollagens type I and III carboxy- and amino-terminal peptides (PICP, PINP, PIIICP, PIIINP), and ECM metabolism controlling factors - tumor growth factor beta-1 (TGF1-ß), and connective tissue growth factor (CTGF) - were measured in serum at baseline, and at 3- and 12-month follow-up. All pts underwent endomyocardial biopsy to determine the presence and extent of ECM fibrosis. RESULTS: Markers of collagen type I synthesis (PICP and PINP) were almost homogenously increased over the 3- and 12-month period, whereas PIIINP values decreased and PIIICP levels were unchanged in new-onset and chronic DCM, and in pts with and without ECM fibrosis. Both TGF-ß and CTGF levels decreased over the observation period. Kinetics of serum markers of collagen synthesis and fibrosis controlling factors did not differ between DCM pts categorized according to disease duration and fibrosis status. CONCLUSIONS: The kinetics of collagen type I and III synthesis in DCM move in opposite directions, with production of collagen type I consistently increasing, and the synthesis of collagen type III decreasing. Levels of TGF and CTGF, which are proven fibrosis-stimulating factors, had a tendency to decrease. Regardless of disease duration or fibrosis status, the kinetics of serum markers of collagen synthesis, TGF and CTGF were similar in DCM. A better understanding of the kinetics of serum markers of fibrosis in DCM may help to develop more tailored therapeutic approaches to fibrosis.

Stenotic Bicuspid and Tricuspid Aortic Valves　- Micro-Computed Tomography and Biological Indices of Calcification.

BACKGROUND: Valve calcification is well estimated by ex-vivo micro-computed tomography (micro-CT). The objective of this study was to investigate the associations between micro-CT findings and biological indices of calcification in aortic stenosis (AS), as well as differences between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV).Methods and Results:Aortic valves and plasma were obtained from patients undergoing valve surgery. Valves were dissected and underwent micro-CT, genetic analyses, and calcium content assessment. Plasma levels of calcification markers were measured. Forty-two patients with isolated severe AS, including 22 with BAV, were studied. BAV patients had a lower median CT value (140.0 [130.0-152.0] vs. 157.0 [147.0-176.0], P=0.002) and high-density calcification (HDC) fraction (9.3 [5.7-23.3] % vs. 21.3 [14.3-31.2] %, P=0.01), as compared with TAV. Calcification fraction (CF) correlated with AS severity (measured as maximal transvalvular pressure gradient [r=0.34, P=0.03], maximal flow velocity [r=0.38, P=0.02], and indexed aortic valve area [r=-0.37, P=0.02]). For TAV patients only, mRNA expression of integrin-binding sialoprotein correlated with CF (r=0.45, P=0.048), and the receptor activator of the nuclear factor κ-B ligand transcript correlated with HDC corrugation (r=0.54, P=0.01). CONCLUSIONS: TAV patients with AS present more mineralized calcifications in micro-CT than BAV subjects. The relative volume of calcifications increases with the AS severity. In TAV patients, upregulated expression of genes involved in osteoblastogenesis in AS correlates with leaflet mineralization in micro-CT.

Left ventricular reverse remodeling is not related to biopsy-detected extracellular matrix fibrosis and serum markers of fibrosis in dilated cardiomyopathy, regardless of the definition used for LVRR.

Left ventricular reverse remodeling (LVRR) is reported in dilated cardiomyopathy (DCM) patients (pts). However, numerous definitions of LVRR exist. Measurements of serum markers of fibrosis provide insight into myocardial fibrosis. The relationship between LVRR and fibrosis is poorly understood. From July 2014 until October 2015, we included 63 consecutive DCM pts (48 ± 12.1 years, EF 24.4 ± 7.4%) with completed baseline and 3-month follow-up echocardiograms. LVRR was assessed on the basis of four differing definitions. Procollagens type I and III carboxy- and amino-terminal peptides (PICP, PINP, PIIICP, and PIIINP), collagen 1, ostepontin, tumor growth factor beta-1, connective tissue growth factor, and matrix metalloproteinases (MMP-2, MMP-9), and their tissue inhibitor (TIMP-1) were measured in serum. In addition, all pts underwent right ventricular endomyocardial biopsy. Depending on the definition chosen, LVRR could be diagnosed in between 14.3 and 50.8% pts. Regardless of the LVRR definition used, the frequency of LVRR was similar in fibrosis negative and positive DCM. Minor differences of markers of fibrosis were detected between pts with and without LVRR. For every LVRR definition, adjusted and unadjusted models were constructed to evaluate the predictive value of serum fibrosis parameters. Only an increase of TIMP-1 by 1 ng/ml was found to independently increase the probability of LVRR by 0.016%. The choice of a particular definition of LVRR determines the final diagnosis, and this has a profound impact on subsequent management. LVRR is unrelated to biopsy-detected ECM fibrosis. Serum markers of fibrosis are only weakly related to LVRR, and are not of use in the prediction of LVRR.

Fibrosis of extracellular matrix is related to the duration of the disease but is unrelated to the dynamics of collagen metabolism in dilated cardiomyopathy.

BACKGROUND: Fibrosis of extracellular matrix (ECM) in dilated cardiomyopathy (DCM) corresponds to the myocardial over-production of various types of collagens. However, mechanism of this process is poorly understood. OBJECTIVE: To investigate whether enhanced metabolism of ECM occur in DCM. METHODS: Seventy consecutive DCM patients (pts) (48 ± 12.1 years, EF 24.4 ± 7.4 %) and 20 healthy volunteers were studied. Based on symptoms duration, pts were divided into new-onset (n = 35, 6 months) and chronic DCM (n = 35, >6 months). Markers of collagen type I and III synthesis-procollagen type I carboxy- and amino-terminal peptides (PICP and PINP) and procollagen type III carboxy- and amino-terminal peptides (PIIICP and PIIINP), collagen 1 (col-1), ECM metabolism controlling factors-tumor growth factor beta-1 (TGF1-ß), connective tissue growth factor (CTGF), and ECM degradation enzymes-matrix metalloproteinases (MMP-2, MMP-9) and their tissue inhibitor (TIMP-1) were measured in serum. All pts underwent right ventricular endomyocardial biopsy to study ECM fibrosis. RESULTS: The presence of fibrosis was detected in 24 (34.3 %) pts and was more prevalent in chronic DCM [17 (48.6 %) vs. 7 (20 %), p < 0.01]. The levels of PIIINP [4.41 (2.17-6.08) vs. 3.32 (1.69-5.02) ng/ml, p < 0.001], CTGF [3.82 (0.48-23.87) vs. 2.37 (0.51-25.32) ng/ml, p < 0.01], MMP-2 [6.06 (2.72-14.8) vs. 4.43 (2.27-7.4) ng/ml, p < 0.001], MMP-9 [1.98 (0.28-9.25) vs. 1.01 (0.29-3.59) ng/ml, p < 0.002)], and TIMP-1 [15.29 (1.8-36.17) vs. 2.61 (1.65-24.09) ng/ml, p < 0.004] were significantly higher in DCM, whereas levels of col-1 [57.7 (23.1-233.4) vs. 159.4 (31.2-512.9) pg/ml, p < 0.001] were significantly lower in DCM compared to controls. There were no differences in all measured serum markers of ECM metabolism between newonset and chronic DCM and as well as fibrosis positive and negative pts. Fibrosis was weakly correlated only with the duration of DCM (r = 0.23, p < 0.05), however, not a single serum marker of fibrosis correlated with fibrosis. Neither unadjusted nor adjusted models, constructed from serum markers of ECM metabolism, predicted the probability of myocardial fibrosis. CONCLUSIONS: Dynamics of ECM turnover in DCM is high, which is reflected by the increased levels CTGF and degradation enzymes. Synthesis of collagen type III prevailed over collagen type I. ECM metabolism was not different in DCM regardless of the duration of the disease and status of myocardial fibrosis. Serum markers of ECM metabolism were found not to be useful for the prediction of myocardial fibrosis in DCM.

Warfarin Metabolites in Patients Following Cardiac Valve Implantation: A Contribution of Clinical and Genetic Factors.

INTRODUCTION: Warfarin, a racemic mixture of S- and R-enantiomers, is the cornerstone of therapy in patients following cardiac valve replacement. S-warfarin is metabolized to 7-S-hydroxywarfarin by the cytochrome P450 isoform 2C9 encoded by CYP2C9 gene. R-warfarin is metabolized by multiple cytochromes P450. We sought to assess the impact of clinical and genetic factors on circulating warfarin metabolites following valve implantation. MATERIAL AND METHODS: Venous blood was collected from 120 patients after 3 months since elective mitral and/or aortic valve replacement. Plasma S-warfarin, R-warfarin, S-7-hydroxywarfarin, and R-7-hydroxywarfarin were determined using high-performance liquid chromatography. The S-7-hydroxywarfarin/S-warfarin and S-warfarin/R-warfarin (S/R) ratios, along with warfarin sensitivity index (WSI), defined as INR/S-warfarin ratio, were calculated. Vitamin K epoxide reductase complex subunit 1 (VKORC1) c.-1639A, CYP2C9*3 and CYP2C9*2 alleles were determined using real-time polymerase chain reaction. RESULTS: The S-warfarin was higher in former smokers (p = 0.047) and the VKORC1 c.-1639A allele carriers (p < 0.0001). The S-7-hydroxywarfarin was lower in carriers of the VKORC1 c.-1639A allele (p = 0.0005) and CYP2C9*3 (p = 0.047). The S-7-hydroxywarfarin/S-warfarin ratio was lower in the carriers of CYP2C9*3 (p = 0.008), but not in those with VKORC1 -c.1639A allele. The S/R ratio was higher in patients with hypertension (p = 0.01). The independent predictors of elevated S/R ratio defined as the upper quartile were diabetes (p = 0.045), CYP2C9*3 (p < 0.0001) and CYP2C9*2 (p = 0.0002). The independent predictors of elevated WSI were current smoking (p = 0.049), implantation of mechanical valve (p = 0.006) and VKORC1c.-1639A allele (p = 0.007). CONCLUSION: We conclude that not only genetic, but also several clinical factors affect warfarin metabolites in patients following cardiac valve implantation.

Association of the C-Reactive Protein Gene (CRP) rs1205 C>T Polymorphism with Aortic Valve Calcification in Patients with Aortic Stenosis.

Elevation in C-reactive protein (CRP) levels have been shown in patients with aortic valve stenosis (AS). Minor allele of the CRP gene (CRP) rs1205 C>T polymorphism has been associated with lower plasma CRP concentrations in cohorts of healthy and atherosclerotic patients. Considering the existing similarities between atherosclerosis and AS, we examined the effect of CRP rs1205 C>T polymorphism on the AS severity. Three hundred consecutive Caucasian patients diagnosed with AS were genotyped for the rs1205 C>T polymorphism using the TaqMan assay. Severity of the AS was assessed using transthoracic echocardiography. The degree of calcification was analyzed semi-quantitatively. Carriers of the rs1205 T allele were characterized by elevated serum CRP levels (2.53 (1.51-3.96) vs. 1.68 (0.98-2.90) mg/L, p<0.001) and a higher proportion of the severe aortic valve calcification (70.4% vs. 55.1%, p=0.01) compared with major homozygotes. The effect of CRP rs1205 polymorphism on CRP levels is opposite in AS-affected than in unaffected subjects, suggesting existence of a disease-specific molecular regulatory mechanism. Furthermore, rs1205 variant allele predisposes to larger aortic valve calcification, potentially being a novel genetic risk marker of disease progression.

Interleukin-6 receptor Asp358Ala gene polymorphism is associated with plasma C-reactive protein levels and severity of aortic valve stenosis.

BACKGROUND: Interleukin-6 receptor (IL-6R) gene Asp358Ala (A>C, rs2228145) polymorphism has been associated with lower circulating inflammation biomarkers in coronary artery disease (CAD), such as C-reactive protein (CRP) or fibrinogen, but its role in the pathogenesis of aortic valve stenosis (AS) remains unknown. Since the pathogenesis of AS and atherosclerosis shares several similarities, we tested the hypothesis that IL-6R Asp358Ala polymorphism is associated with the severity of AS. METHODS: A total of 284 AS patients aged 64.3±11.1 years were studied, in whom IL-6R polymorphism was determined by TaqMan genotyping. RESULTS: The genotype distribution was as follows: AA-43.7% (n=124); AC-37.0% (n=105); and CC-19.4% (n=55). For every copy of C allele inherited, mean concentration of CRP was reduced by 22% (95% CI 13.8-30.4; p<0.0001). Carriers of the C allele compared to the AA homozygotes were also characterized by lower mean and maximal transvalvular gradients [44.8 (30.5-60.0) vs. 52.7 (40.5-69.0) mmHg, p=0.0005; and 78.1±26.5 vs. 87.3±27.6 mmHg; p=0.008, respectively], and larger aortic valve area [0.8 (0.6-1.0) vs. 0.7 (0.5-0.9) cm2, p=0.005]. CONCLUSIONS: Our study is the first to show that the presence of the IL-6R 358Ala allele in AS patients is associated with attenuated systemic inflammatory state and less severe AS.

The First Potentially Causal Genetic Variant Documented in a Polish Woman with Multiple Cavernous Malformations of the Brain.

Cerebral cavernous malformations (CCMs) are relatively common in the central nervous system. They occur in two forms, sporadic and familial (FCCMs). Three genes are recognized to be associated with FCCM, including CCM1, CCM2, and CCM3, the latter also called PDCD10. In this article, we describe a single-nucleotide variant in the PDCD10 gene in a 23-year-old Polish female with CCM. The NM_007217.4 (PDCD10): c.395+1G>A variant destroys the canonical splice donor site following exon 6. This is the first reported genetically characterized case of CCM (FCCM) in Poland.

Link between fibrosis-specific biomarkers and interstitial fibrosis in hypertrophic cardiomyopathy.

BACKGROUND: Cardiac fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and has confirmed unfavorable clinical significance. Replacement fibrosis is better known and has already been studied on a larger scale, whereas interstitial fibrosis is less explored. AIMS: We aimed to analyze the relationship between serum biomarkers and interstitial fibrosis, as assessed with cardiac magnetic resonance (CMR) in HCM patients. METHODS: We performed 3T CMR scans in 50 HCM patients to assess interstitial fibrosis as expressed by extracellular volume (ECV). In all patients, we determined levels of serum cardiac-specific (troponin T [TnT], N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) and fibrosis-specific (procollagen I C-terminal propeptide, procollagen III N-terminal propeptide, transforming growth factor ß1, galectin-3) biomarkers. Patients were divided based on their median value of ECV. RESULTS: The final study population included 49 patients. The median value of ECV in our cohort was 28.1%. Patients stratified according to median ECV differed in terms of several variables: body mass index, late gadolinium extent, NT-proBNP, and galectin-3 levels (all P <0.05). Cardiac biomarkers (TnT and NT-proBNP) and galectin-3 were significantly correlated with ECV (rS = 0.34; P = 0.02; rS = 0.39; P = 0.006; rS = 0.43; P = 0.002, respectively). Galectin-3 and body mass index were found to be independent predictors of ECV (odds ratio [OR], 2.29 [1.07-4.91]; P = 0.03; OR, 0.81 [0.68-0.97]; P = 0.02, respectively). CONCLUSIONS: Galectin-3 was an independent predictor of interstitial fibrosis in HCM patients expressed as elevated ECV values. The other measured fibrosis-specific biomarkers were not useful in detecting interstitial fibrosis in HCM. In addition, there was a positive correlation between classical cardiac biomarkers and interstitial fibrosis in HCM patients.